Ti-TADDOLates

Seeeach et al. also investigated the Ti-TADDOlate-catalyzed Diels-Alder reaction, see D. Seeeach, R. Dahinden,... 

Scheme 3.56 CPG-Immobilised sulfur-containing Ti-TADDOLate for butylation of benzaldehyde.

Scheme 10.8 1,3-Dipolar cycloaddition in presence of CPG-immobilised Ti-TADDOLate.

Employing 0.2 equiv. of polymer-bound dendritic Ti-TADDOLates of type 89 (1st and 2nd generation) enantioselectivities up to 98 2 were observed (Fig. 31). This value is comparable to those obtained in heterogeneous reactions using non-dendritic, polymer-bound analogs 88 (er up to 98,5 1,5 [ 105 ]) and with the... 

Fig. 31. Selectivity comparison for the enantioselective addition of Et2Zn to benzaldehyde using different dendritic and non-dendritic homogeneous and heterogeneous Ti-TADDOLates as chiral catalysts [107,110], (S)-.(R) ratios refer to the 1-phenyl-propanol formed...

A comparison of the rates showed that the polymer-bound Ti-TADDOLate 88 and the dendritic polymer 89 catalyze the Et2Zn-to-PhCHO addition at a similar fast rate as the monomeric TADDOLate 86 and the dendritic TADDOLate 87 in homogeneous solution [107,112]. Further experiments also with other ligands are being carried out in our laboratories. 

Figure 9 Supported Ti-TADDOLate catalyst for enantioselective addition of diethylzinc to benzaldehyde...

The role of Ti(OPri)4 in this process is shown in Figure 2-7. The aldehyde is illustrated in two conformations, the solid lines indicating the more favorable orientation. The conformation represented by the dashed line is disfavored by a steric interaction with a pseudo-axial aryl group. Assuming that the attack of a nucleophile comes from the direction of the viewer, this hypothesis accounts for the Sf-face selectivity in all known Ti-TADDOLate-mediated nucleophilic additions to aldehydes. 

The Sharpless reagent, i.e. Ti(OPr-i)4/TBHP/diethyl tartrate, has been tested in the asymmetric BV oxidation of mono and bicyclic butanones . Conversions are low in all cases and ee values range from moderate to good. The best result has been obtained with the most bulky bicyclic ketone of the series, oxidized to the corresponding lactone with ee values up to 75%, using (+)-diethyl tartrate as ligand (equation 79). The use of a modified Sharpless reagent, based on Ti-TADDOL catalyst , increased the reaction rates, but decreased the enantiomeric excesses . ... 

Enantioselective alkenylation was first reported by Oppolzer and Nadinov. Divinylzinc adds to aldehydes in the presence of the chiral diamino alcohol catalyst 37 with high enantioselectivity (>96% ) (equation 16)51. Alkenylzinc bromide adds to aldehydes in the presence of the lithium alkoxide of /V-methylephcdrinc (>98% )52. Ti-TADDOL is also an effective chiral catalyst in the addition of divinylzinc53. 

Various a,a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanols have been prepared from (R,R)-tartrate, which are called TADDOLs by Seebach et al. They studied the influence of the Ti catalyst preparation methods, the presence of molecular sieves, and the TADDOL structure in the enantioselective Diels-Alder reaction of acryloyl oxazolidinones [41] (Eq. 8A.22). Seebach also prepared polymer- and dendrimer-bound Ti-TADDOLates and used in catalytic asymmetric cycloadditions [42],... 

J0rgensen successfully determined the structure of a Ti-TADDOLate/dienophile complex by X-ray crystallography and proposed a possible reaction mechanism for the enantioselective Diels-Alder addition of cyclopentadiene to /V-acyloxazolidinones using the Ti-TADDOLate catalyst [43],... 

More recently, a Ti-TADDOLate catalyst was found useful for a similar asymmetric transformation, and this reaction has been successfully applied to the asymmetric synthesis of the potent, non-peptidic, NKl-selective, substance P antagonist RPR 107880 [59] (Eq. 8A.35). 

Conversions and enanhoselechvihes of CPG-immobilized Ti-TADDOLates match the results observed with unsupported catalysts under similar but homogeneous condihons, a finding also observed in other situations (for references, see the next section) ... 

Scheme 6. First enantioselective electrophilic fluorination reaction catalysed by enantiopure Ti-TADDOLates 33a,b. The absolute configuration of the product is unknown.

Finally, two substoichiometric chiral systems are available, but limited success has been achieved thus far. The cyclohexyldisulfonamide system 21 converts allylic alcohols to cyclopropanes in ee s up to 89% (Equation 13.7, Protocol 12)35,36 whereas the Ti-TADDOLATE 25 converts 3-aryl substituted allylic alcohols in ee s up to 91% (Scheme 13.3, Protocol 13).37 Both of these reactions are very capricious and the level of enantiomeric purity is highly substrate-dependent. However, it is anticipated that even more effective and general catalysts will emerge in the next few years. 

In contrast the polymer-bound Ti-TADDOLates are very effective D. Seebach, R, E. Marti, T. Hin-terinann, Helv. Chim. Acta. 1996, 79, 1710. 

Introduction. Ti-TADDOLates are a,a,a, a -tetraaryl-2,2-disubstituted l,3-dioxolane-4,5-dimethanolatotitanium derivatives. The most common substituents are R, R = Me/Me and Ph/Me, Ar=Ph and 2-naphthyl, X, Y = C1/C1, t-PrO/Cl, Cp/Cl, and i-PrO/i-PtO. The corresponding TADDOLs (2) are available in both enantiomeric forms from tartrate esters which are acetalized (R R CO) and allowed to react with aryl Grignard reagents. The reactions performed in the presence of Ti-TADDOLates or with Ti-TADDOLate derivatives include nucleophilic additions to aldehydes - - and nitroalkenes of alkyl, aryl, and allylic - groups aldol additions hydrophosphonylations and cyanohydrin reactions of aldehydes inter- and intramolecular Diels-Alder additions ... 

Preparation of Ti-TADDOLate Solutions. Five different procedures have been mostly used for the preparation of TAD-DOLates (1). 

An additional procedure leading from a titanate (1) (X = Y = i-PrO) to the corresponding dichloride (X = Y = Cl) is to treat the former with Tetrachlorosilane and pump off (i-PrO)2SiCl2. A method in which the Ti-TADDOLate is present together with another Lewis acid Lithium Chloride) is to treat a TADDOL (2) with 2 equiv n-Butyllithium, followed by TiCU. ... 

As in other applications of 7V-acyl-l,3-oxazolidin-2-ones, 2-thiones, and sthiazolidine-2-thiones, chelation of the Lewis acid center for restricted rotation is considered decisive for the reactions occurring under the influence of the Ti-TADDOLates. Generally, the attack of the nucleophilic component (diene or ene) on the chelated electrophile occurs from the bottom face if the chelate ring is drawn as shown in structures (17) and (18), (19), and (lO). For the oxazolidinones, this means that the trigonal a-carbonyl center is approached from the (/ e)-face when an (/ ,/ )-Ti-TADDOLate is used (rel. topicity like) the mechanism of this reaction has been discussed. ... 

Other Enantioselective Transformations Mediated by Ti-TADDOLates. The iodolactonization of 2-allyl-2-hydroxy-4-pentenoic acid shown in eq 8 gives (21) in a 67% yield (after cyclization of some iodo isopropyl ester formed as a side product), the iodolactone is a single (—)-diastereoisomer with a 5 1 (S,S)I(R,R) ratio. The TADDOLate generated in situ was employed in stoichiometric amount. The two enantiomers of 2-pyridyl 2-phenylthiobutyrate react with a rate difference of 39 1 with excess isopropanol in the presence of 0.1 equiv of a Ti-TADDOLate under the conditions specified in eq 9. This leads to the isopropyl ester (22) containing 96% of the (/ )-enantiomer... 

Other important titanium alkoxide-based Lewis acids are Ti-TADDOLate (a,a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol)ates, among the most effective chiral catalysts for several important asymmetric reactions. These will be discussed in the sections on polymer-supported Diels-Alder reactions (Section 21.10) and alkylations (Section 21.9). 

Since the first report on Ti-TADDOLate-mediated Diels-Alder reactions [97,98] several studies of the same reaction have been reported these have shown that Ti-TADDOLate is an efficient chiral Lewis acid in enantioselective Diels-Alder reactions. Polymer- and dendrimer-supported Ti-TADDOLates have been reported and their catalytic activity in several enantioselective reactions has been evaluated [59]. Various kinds of polymeric TADDOLs were prepared both by chemical modification (Eq. 22) and by copolymerization (Eq. 23). 

Polymer-supported TADDOL-Ti catalyst 79 prepared by chemical modification was poorly active in the Diels-Alder reaction of 3-crotonoyloxazolidinone with cyclo-pentadiene (Eq. 24) whereas polymeric TADDOL-Ti 81 prepared by copolymerization of TADDOL monomer 80 with styrene and divinylbenzene had high activity similar to that of the soluble catalyst. In the presence of 0.2 equiv. 81 (R = H, Aryl = 2-naphthyl) the Diels-Alder adduct was obtained in 92 % yield with an endolexo ratio of 87 13. The enantioseleetivity of the endo product was 56 % ee. The stability and recyclability of the catalyst were tested in a batch system. The degree of conversion, the endolexo selectivity, and the enantioseleetivity hardly changed even after nine runs. Similar polymer-supported Ti-TADDOLate 82 was prepared by the chemical modification method [99]. Although this polymer efficiently catalyzed the same reaction to give the (2R,2S) adduct as a main product, asymmetric induction was less than that obtained by use of a with similar homogeneous species. 

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